The effects of short-term overfeeding on energy expenditure and nutrient oxidation in obesity-prone and obesity-resistant individuals.

OBJECTIVE: The roles that energy expenditure (EE) and nutrient oxidation play in a predisposition for weight gain in humans remains unclear. SUBJECTS: We measured EE and respiratory exchange ratio (RER) in non-obese obesity-prone (OP; n=22) and obesity-resistant (OR; n=30) men and women following a eucaloric (EU) diet and after 3 days of overfeeding (1.4 × basal energy). RESULTS: Twenty-four hour EE, adjusted for fat-free mass and sex, measured while consuming a EU diet was not different between OP and OR subjects (2367±80 vs 2285±98 kcals; P=0.53). Following overfeeding, EE increased in both OP and OR (OP: 2506±63.7, P<0.01; OR: 2386±99 kcals, P<0.05). Overfeeding resulted in an increase in 24-hour RER (OP: 0.857±0.01 to 0.893±0.01, P=0.01; OR: 0.852±0.01 to 0.886±0.01, P=0.005), with no difference between groups in either the EU or overfeeding conditions (P>0.05). Nighttime RER (∼10pm-6:30am) did not change with overfeeding in OR (0.823±0.02 vs 0.837±0.01, P=0.29), but increased significantly in OP subjects (0.798±0.15 to 0.839±0.15, P<0.05), suggesting that fat oxidation during the night was downregulated to a greater extent in OP subjects following a brief period of overfeeding, as compared with OR subjects who appeared to maintain their usual rate of fat oxidation. Protein oxidation increased significantly in both OP (P<0.001) and OR (P<0.01) with overfeeding, with no differences between OP and OR. CONCLUSION: These results support the idea that overfeeding a mixed diet results in increases in EE and RER, but these increases in EE and RER are likely not responsible for obesity resistance. Adaptive responses to overfeeding that occur during the night may have a role in opposing weight gain.

Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein.

Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics.

To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [(3)H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened in 475 individuals from five ethnic groups and 90 European Caucasian cancer patients treated with paclitaxel. Only OATP1B3 was capable of transporting paclitaxel to a significant extent (P=0.003). The 334T>G and 699G>A SNPs were less common in the African-American and Ghanaian populations (P<0.000001). Paclitaxel pharmacokinetics were not associated with the studied SNPs or haplotypes (P>0.3). The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.

Prolonged fasting significantly changes nutrient oxidation and glucose tolerance after a normal mixed meal.

The aim of this study was to establish the experimental paradigm of fasting, followed by refeeding, to investigate individual differences in nutrient partitioning. Eight nonobese men were fed a normal meal (25% of daily energy requirements) on two occasions, after an overnight (13-h) fast and after a prolonged (72-h) fast. During the entire fasting period, subjects were resident in a whole room indirect calorimeter, and blood samples were drawn periodically. Because no other food was consumed over the 12 h after either meal, negative energy balance was observed after the overnight and prolonged fast. Postprandial carbohydrate oxidation was significantly reduced after the 72- vs. 13-h fast (P < 0.0001), whereas fat oxidation was significantly increased (P < 0.0001). Interestingly, carbohydrate balance was positive after the prolonged fast but negative after the overnight fast (24 +/- 17 vs. -57 +/- 16 g/12 h, respectively; P < 0.001), whereas fat balance was negative under both conditions (-78 +/- 7 vs. -47 +/- 8 g/12 h, respectively; P < 0.002). With 72 h of fasting, the glucose and insulin excursions in response to the mixed meal were significantly greater compared with the 13-h fast (P < 0.001). In conclusion, prolonged fasting resulted in a significant decrease in carbohydrate oxidation and an increase in fat oxidation, after a normal mixed meal, in healthy men. This was associated with a significant decrease in glucose tolerance. Because circulating free fatty acids were greatly elevated at all times after the prolonged fast, these may be mediating some of the changes in postprandial metabolism.

Fuel metabolism in men and women during and after long-duration exercise.

This study aimed to determine gender-based differences in fuel metabolism in response to long-duration exercise. Fuel oxidation and the metabolic response to exercise were compared in men (n = 14) and women (n = 13) during 2 h (40% of maximal O2 uptake) of cycling and 2 h of postexercise recovery. In addition, subjects completed a separate control day on which no exercise was performed. Fuel oxidation was measured using indirect calorimetry, and blood samples were drawn for the determination of circulating substrate and hormone levels. During exercise, women derived proportionally more of the total energy expended from fat oxidation (50.9 +/- 1.8 and 43. 7 +/- 2.1% for women and men, respectively, P < 0.02), whereas men derived proportionally more energy from carbohydrate oxidation (53.1 +/- 2.1 and 45.7 +/- 1.8% for men and women, respectively, P < 0.01). These gender-based differences were not observed before exercise, after exercise, or on the control day. Epinephrine (P < 0.007) and norepinephrine (P < 0.0009) levels were significantly greater during exercise in men than in women (peak epinephrine concentrations: 208 +/- 36 and 121 +/- 15 pg/ml in men and women, respectively; peak norepinephrine concentrations: 924 +/- 125 and 659 +/- 68 pg/ml in men and women, respectively). As circulating glycerol levels were not different between the two groups, this suggests that women may be more sensitive to the lipolytic action of the catecholamines. In conclusion, these data support the view that different priorities are placed on lipid and carbohydrate oxidation during exercise in men and women and that these gender-based differences extend to the catecholamine response to exercise.

Female rats do not develop sucrose-induced insulin resistance.

In male rats, 2 wk of high-sucrose feeding results in insulin resistance and hypertriglyceridemia [Pagliassotti, M.J., P.A. Prach, T.A. Koppenhafer, and D.A. Pan. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R1319-R1326, 1996]. The present study aimed to determine if female rats also become insulin resistant and hypertriglyceridemic in response to high-sucrose feeding. Female Wistar rats (7 wk old) were fed either a high-sucrose diet (68% energy) (SU) or a high-starch diet (68% energy) (ST) for 3, 5, or 8 wk. In each animal, glucose kinetics were measured using [3-(3)H]glucose under basal and hyperinsulinemic conditions (insulin infusion 4.0 mU.kg-1.min-1). Body weight and basal glucose kinetics were not different between diet groups at 3, 5, or 8 wk. Glucose infusion rate (mg.kg-1.min-1) was not different between groups (3 wk: 17.7 +/- 1.6 ST, 16.6 +/- 0.9 SU; 5 wk: 16.1 +/- 0.9 ST, 15.1 +/- 2.0 SU; 8 wk: 18.3 +/- 1.9 ST, 16.1 +/- 1.5 SU). Clamp rate of glucose appearance (mg.kg-1.min-1) was also not different between diet groups (3 wk: 4.0 +/- 1.6 ST, 3.6 +/- 1.4 SU; 5 wk: 2.6 +/- 1.0 ST, 2.3 +/- 1.14 SU; 8 wk: 5.9 +/- 1.8 ST, 7.7 +/- 1.2 SU). No difference was observed in plasma and tissue triglycerides or tissue glycogen between sucrose- and starch-fed animals. We therefore conclude that female rats, in contrast to males, do not develop sucrose-induced insulin resistance and hypertriglyceridemia.

Reduced insulin suppression of glucose appearance is related to susceptibility to dietary obesity in rats.

To examine the relationship between insulin action and body weight regulation in male rats, the following studies were performed. In study 1, rats (n = 31) were fed a low-fat diet (LFD) for 4 wk, and then glucose kinetics were estimated under basal and hyperinsulinemic conditions using the glucose clamp. After clamps, these same rats were placed on a high-fat diet (HFD) for 5 wk. In study 2, rats (n = 30) were fed an LFD for 3 wk and then a high-sucrose diet for 1 wk to produce selective hepatic insulin resistance. Clamps were then performed, and after clamps, these same rats were placed on an HFD for 5 wk. In study 3, rats (n = 30) were fed an LFD for 1 wk and then a high-sucrose diet for 3 wk to produce widespread insulin resistance. Clamps were then performed, and after clamps, these same rats were placed on an HFD for 5 wk. The rate of glucose appearance (R(a)) during the hyperinsulinemic clamps was the only pre-HFD variable that correlated (r = 0.49, P < 0.01 in study 1; r = 0.51, P < 0.001 in study 2) with weight gain on the HFD. Clamp R(a) also correlated with energy intake on the HFD in study 1 (r = 0.64, P < 0.001) and study 2 (r = 0.59, P < 0.001). Clamp R(a) and energy intake on the HFD accounted for similar portions of the variance in body weight gain on the HFD. Weight gain and fat-pad mass were increased (P < 0.05) in study 2 compared with study 1. In study 3, pre-HFD glucose kinetics were not correlated with energy intake or weight gain on the HFD. Widespread insulin resistance did not significantly reduce the rate of weight gain on the HFD. Thus insulin action on R(a) can influence body weight gain on an HFD. The effects of R(a) on body weight gain appear to be mediated via effects on energy intake. Selective hepatic insulin resistance can increase body weight gain on an HFD, but widespread insulin resistance does not significantly reduce HFD-induced weight gain.

Post-prandial thermogenesis with ephedrine, caffeine and aspirin in lean, pre-disposed obese and obese women.

OBJECTIVE: To determine whether or not aspirin further potentiates the greater post-prandial thermogenesis induced by ephedrine with caffeine. DESIGN: Determination of the acute metabolic rate response to the following treatments: 1050 kJ liquid meal (M); meal plus ephedrine (30 mg) and caffeine (100 mg) (MEC) or meal plus ephedrine, caffeine and aspirin (300 mg) (MECA). SUBJECTS: Lean, pre-disposed obese and obese women (n = 10 each group). MEASUREMENTS: Pre- and post-treatment metabolic rate determinations via indirect calorimetry. Post-treatment measurements made at 20 min intervals for a total of 160 min. RESULTS: In all groups, metabolic rate increased significantly more following the MEC or MECA, compared to the meal only (p < 0.05). The obese group had a significantly greater absolute increase in metabolic rate following the MECA and MEC compared to both the lean and pre-disposed obese groups (p < 0.05). Metabolic rate remained elevated at the end of the 160 min following all treatments. CONCLUSION: Aspirin does not further potentiate the acute thermic effect of ephedrine and caffeine with a meal. However, the full thermogenic response was not measured and longer duration studies are necessary to confirm these results.

Fat and carbohydrate overfeeding in humans: different effects on energy storage.

Both the amount and composition of food eaten influence body-weight regulation. The purpose of this study was to determine whether and by what mechanism excess dietary fat leads to greater fat accumulation than does excess dietary carbohydrate. We overfed isoenergetic amounts (50% above energy requirements) of fat and carbohydrate (for 14 d each) to nine lean and seven obese men. A whole-room calorimeter was used to measure energy expenditure and nutrient oxidation on days 0, 1, 7, and 14 of each overfeeding period. From energy and nutrient balances (intake-expenditure) we estimated the amount and composition of energy stored. Carbohydrate overfeeding produced progressive increases in carbohydrate oxidation and total energy expenditure resulting in 75-85% of excess energy being stored. Alternatively, fat overfeeding had minimal effects on fat oxidation and total energy expenditure, leading to storage of 90-95% of excess energy. Excess dietary fat leads to greater fat accumulation than does excess dietary carbohydrate, and the difference was greatest early in the overfeeding period.

Energy balance in endurance-trained female cyclists and untrained controls.

Reports of low energy intakes in trained female athletes imply they have an increased energetic efficiency. To address this question, we determined how energy balance was achieved in endurance-trained females cyclists and lean controls (n = 5 in each group). Daily energy expenditure was measured by using standardized physical activity protocols in a whole room calorimeter on two separate occasions: a cycling day and a noncycling day. Energy intake for weight maintenance was determined by a period of controlled feeding 5 days before and the day of each energy expenditure measurement. Energy balance was achieved in the cyclists on the cycling day while they consumed 2,900-3,000 kcal (their usual condition) and in controls on the noncycling day while they consumed 2,100-2,200 kcal (their usual condition). Total daily energy expenditure was not significantly different between the cyclists and controls on the noncycling day with both groups performing similar levels of activity. On the cycling day, daily energy expenditure was significantly greater in the cyclists vs. controls (P < 0.03) as a result of their greater amount of cycling activity. Components of daily energy expenditure, i.e., resting metabolic rate and thermic effect of food and activity (noncycling), were not significantly different between groups. Overall, we found no significant increase in the energetic efficiency of endurance-trained female cyclists compared with controls.

Effect of habitual exercise on daily energy expenditure and metabolic rate during standardized activity.

To assess whether long-term habitual exercise affects energy expenditure even on a nontraining day, 24-h energy expenditure (24-h EE) and metabolic rate of sedentary, moderately active, and highly active males (n = 10 per matched group), were measured in a room respirometer on two separate occasions: sedentary and standardized mild-exercise protocols. Twenty-four--hour EE was greatest in the highly active group, second highest in the moderately active group, and lowest in the sedentary group on both experimental days (sedentary day: 9908 +/- 344, 9328 +/- 357, and 8669 +/- 227 kJ/d; exercise day: 11915 +/- 395, 11609 +/- 328, and 11063 +/- 370 kJ/d, respectively). Differences were significant between the 24-h EE (P < 0.01), waking (P < 0.03), and sleeping metabolic rate (P < 0.01) of the highly active group compared with the sedentary group. However, when expressed per unit lean body mass (LBM), group values on both experimental days were not significantly different. Therefore, we found no evidence that habitual exercise, at a high or moderate level, leads to a significant prolonged stimulation of metabolic rate per unit active tissue. However, the increased LBM associated with exercise does increase daily energy expenditure by 8-14%.

Aspirin potentiates the effect of ephedrine on the thermogenic response to a meal in obese but not lean women.

The effect of ephedrine (30 mg) and aspirin (300 mg) on the acute thermogenic response to a liquid meal (250 kcal) was investigated in lean and obese women (n = 10 each group). Resting metabolic rate (RMR) was measured prior to each of the following treatments: meal only (M), meal plus ephedrine (ME) or meal plus ephedrine and aspirin (MEA). Eight post-treatment measurements of metabolic rate were made over a total of 160 minutes. Rise in post-treatment metabolic rate was compared to the baseline RMR. Following the M treatment, the mean increase in metabolic rate was 0.17 +/- 0.01 and 0.13 +/- 0.02 kcal/min in the lean and obese groups respectively, with the corresponding rises being 0.21 +/- 0.02 and 0.19 +/- 0.02 kcal/min following the ME, and 0.23 +/- 0.03 and 0.23 +/- 0.01 kcal/min following the MEA. The increase in post-prandial thermogenesis with the ephedrine or ephedrine plus aspirin was significant in the obese group (P less than 0.03 and P less than 0.001 respectively) but not the lean. Furthermore, the post-treatment rise in metabolic rate, following the MEA treatment compared to the ME, was significantly greater for the obese group (P less than 0.05) but not the lean. It was concluded that aspirin potentiates the stimulatory effect of ephedrine on the thermogenic response to a meal in obese but not lean women.